It has become clear in recent years that there is a high degree of complexity in opioid systems in mammalian brain and peripheral tissues, with evidence for substantial multiplicity of potential endogenous opioid receptor ligands, and for a corresponding complexity in the ligand binding selectivities of various types of specific opioid receptor. In several cases there is evidence for the existence of more than one opioid receptor type in a single tissue, each apparently regulating the same function. Thus the physiological significance of the observed multiplicity of ligands and binding sites, and its relevance to the processes underlying opioid tolerance and dependence requires further study. Two sets of experiments are proposed here. I. Further studies of the apparent receptor heterogeneity include the development of methods for measurement of the binding of dynorphin, a recently isolated and very potent opioid peptide found in brain and other tissues, to receptors with selectivity for this particular peptide, the re-evaluation of the apparent receptor heterogeneity under more physiological conditions, and consideration of possible transitions between different receptor types under tolerance and dependence include further analysis of the particular roles of individual receptor types in the development of the tolerant, dependent state, and of changes in the properties of receptors or receptor-ligand complexes in tolerance and dependence. The proposed studies should provide a better understanding of the physiological role of endogenous opioid systems, perhaps leading to improved therapeutic use of opiate drugs. They should also give insight into the processes underlying opiate drug dependence and possible therapeutic approaches facilitating a return to a stable drug-free condition.